Inhibition of fatty acid amidohydrolase (FAAH), the enzyme responsible for the selective in vivo degradation of the endocannabinoid anandamide, elicits CB1 receptor-mediated anxiolytic, analgesic and cardiovascular depressor effects, without inducing behavioral effects that would indicate addictive potential. In collaboration with Dr. Alex Makriyannis, we have developed and patented a novel FAAH inhibitor, AM3506. AM3506 is highly potent and selective as a FAAH inhibitor, but does not inhibit FAAH in the liver due to its very rapid uptake and metabolism by hepatocytes. This unique feature offers a therapeutic advantage because, unlike other FAAH inhibitors such as URB597, AM3506 does not induce glucose intolerance and insulin resistance, as documented earlier (Godlewski et al., Chemistry & Biology, 2010). We have used AM3506 in a collaborative study with Dr. Andrew Holmes' group, to test its therapeutic potential in posttraumatic shock syndrome, using a mouse model of fear extinction. Endocannabinoids acting via CB1 receptors in the amygdala have been implicated in the extinction of aversive memories (Nature 418:530, 2002), a process that plays a central role in post-traumatic stress syndrome (PTSD). Systemic or intra-amygdala administration of AM3506, which elevated anandamide levels in the amygdala, facilitated fear extinction, and this effect was reversed by CB1 antagonist treatment. In human subjects, individuals carrying a low-expressing FAAH variant showed quicker habituation in a fear-related fMRI task as well as lower stress reactivity in a personality test. These results raise the possible therapeutic use of AM3506 in PTSD. These findings have now been published in Molecular Psychiatry with Dr. Holmes as corresponding author. Endocannabinoids and CB1 receptors have also been implicated in the control of pain responses as analgesic mediators. In collaboration with Dr. Yun Guan (Johns Hopkins Univ) we examined the analgesic properties of AM3506 in a rat model of neuropathic pain. Preliminary findings indicate that AM3506 treatment causes significant, CB1 receptor-mediated reduction in mechanical allodynia, but does not affect thermal hypersensitivity. Additional studies using a rat model of inflammatory pain indicate that AM3506 is ineffective as an analgesic in this model. These findings highlight the selectivity of anandamide action on different modalities of neuropathic pain. Although CB2 receptors were originally discovered and identified as the 'peripheral' cannabinoid receptor, recent studies demonstrated the presence of CB2 receptors in some neurons in the brain. Furthermore, the results of a very interesting recent paper indicate that pharmacological activation of CB2 receptors in the CNS nucleus accumbens inhibitds cocaine self-administration adn some of the centrally mediated effects of cocaine (Nat Neurosci 14:1160, 2011). We therefore decided to test whether treatment of C57Bl6 mice, which have a high preference for alcohol in a two-bottle, free choice paradigm, with a brain penetrant CB2 agonist influences alcohol intake and whether CB2 knockout mice display altered ethanol preference. Preliminary findings indicate that preference for as well as intake of ethanol offered as an unsweetened 15 or 20% ethanol solution is significantly lower in CB2 knockout mice than in wild-type littermates. This unexpected finding suggests that CB2 receptors may tonically increase alcohol preference in this paradigm. Further studies using CB2 agonists and antagonists are in progress.